1. Field of the Invention
The present invention is directed to novel 2- and 5-alkyl and phenyl substituted 4-(1-hydroxy-, 1-acyloxy-, or 1-carbamoyloxy)-2(5H)-furanones which compounds are active as anti-inflammatory agents. The present invention is also directed to pharmaceutical compositions which comprise one or more of the novel compounds of the invention, to the methods of using these pharmaceutical compositions, and to the chemical processes of making the novel compounds.
2. Brief Description of the Prior Art
Manoalide is a compound isolated from a marine sponge [E. D. de Silva et al., Tetrahedron Letters 21:1611-1614 (1980)] which has anti-inflammatory, immunosuppressive and analgesic properties. Manoalide the structure of which is shown below, includes a 5-hydroxy-2(5H)-furanone moiety, attached in the 4-position of the furanone ring to the rest of the molecule. Certain analogs of manoalide, such as seco-manoalide and dehydro-seco-manoalide also have anti-inflammatory activity. For further description of the biological activity of manoalide and some of its derivatives reference is made to U.S. Pat. Nos. 4,447,445, 4,786,651, 4,789,749 and to European Patent Application No. 0 133 376 (published on Feb. 20, 1985). ##STR2##
Synthetic analogs of manoalide, particularly analogs having various substituents on the furanone moiety of manoalide, are described in several United States patents and applications for United States patent assigned to the same assignee as the present application. Among these, U.S. Pat. No. 5,045,564 discloses 4-substituted 2-5(H)-furanones as anti-inflammatory and calcium channel antagonist agents. U.S. Pat. No. 5,183,906 (issued on Feb. 2, 1993) 3 and 5 alkyl and phenyl 4-(1-hydroxy, 1-acyloxy or 1-carbamoyloxy)-5-hydroxy-2-furanones, as anti-inflammatory and calcium channel antagonist agents.
U.S. Pat. No. 5,268,387 describes a method for treating an imbalance between bone production and resorption with furanone compounds, the general examples of which include 3 and 5 alkyl and phenyl 4-(1-hydroxy, 1-acyloxy or 1-carbamoyloxy)-2-furanones, and the specific examples of which include 3 and 5 alkyl and phenyl 4-(1-hydroxy, 1-acyloxy or 1-carbamoyloxy)-5-hydroxy-2-furanones.
European Patent Application No. 0 534 907 A1 (published Mar. 31, 1993) discloses 3,5-dialkyl, 3,5,-dialkyl-4-hydroxy, and 3,4,5-trialkyl-2-furanones as agents for treatment of autoimmune diseases.
As further general background Published European Patent Application No. 0 295 056 is noted, which discloses 4-substituted 5-hydroxy-2(5H)-furanones having anti-inflammatory, immunosuppressive and anti-proliferative activity where the substituents in the 4 position are a variety 1-hydroxyalkyl, 1-acyloxy-alkyl and 1-carbamoyloxy-alkyl groups.
U.S. Pat. No. 4,855,320 discloses 5-arylalkyl-4-alkoxy-2(5H)-furanones as anti-convulsive and anti-epileptic agents.
Published European Patent Application No. 0 209 274 discloses 4-alkyl-5-hydroxy-2(5H)-furanones as anti-inflammatory and anti-allergy agents.
Chemical Abstracts Volume 107 236559t (1987) discloses 4-acyloxy 5-hydroxy-2(5H)-furanones.
2-Substituted 4-furaldehydes (5-substituted 3-furaldehydes) are described in U.S. Pat. No. 4,935,530.